Fluoxetine asymmetric hydrogenation

The procedure for getting the polymer-bound ligands is very easy to reproduce. Three jS-functionalized aromatic ketones were successfully reduced to the corresponding alcohols by heterogeneous asymmetric hydrogen transfer reaction with formic acid-triethylamine azeotrope as the hydrogen donor. One of the product alcohols (19c) is an intermediate for the synthesis of optically active fluoxetine. 

Besides the production of (R)-l-phenylethanol as a fragrance,198 various pharmaceutically important chiral compounds have been produced at various lab scales by asymmetric hydrogenation with JST catalysts. These compounds include a P1-receptor antagonist denopamine hydrochloride (149),191 antidepressant fluoxetine hydrochloride (150),191 antipsychotic BMS 181100 (151),191 serotonin and norepinephrine inhibitor duloxetine (129),164 antihistaminic and anticholinergic orphenadrine (152),192 and antihistaminic neobenodine (153).192... 

The possible amino ketone precursors (186b and 186h) for the synthesis of both (5)-fluoxetine and (5)-duloxetine, respectively, were subjected to gram-scale asymmetric hydrogenation with a high substrate-to-catalyst ratio (S/C = 6000). Both products were obtained in 75% yield with 98% and >99% ee, respectively. The y-amino alcohols obtained could be converted to these important antidepressants in a single step. 

The asymmetric hydrogenation of several / -amino ketones in toluene-water mixture is catalysed by the chiral complex RuPHOX-Ru (43), stable in air and moisture, in the presence of KOH to corresponding y-amino alcohols with up to 99.9% ee. The key intermediates of fluoxetine, tomoxetine, and nisoxetine were obtained in quantitative yield and in up to 99.9% ee ... 

Asymmetric reduction of or y-functionalized alkyl aryl ketones provides a wide variety of chiral amino alcohols. Commercial -chloropropiophenone is reduced with borane-tetrahydrofuran adduct catalyzed by oxazaborolidine 45 to provide the chlorohydrin in over 99 % yield with 94 % ee. The resulting alcohol is a key intermediate for synthesis of the R form of fluoxetine (Prozac ), a serotonin-uptake inhibitor [53]. Using hydrogenation processes the functionalized amino ketones are converted directly into the respective products [8, 43e],... 

---